A rare presentation of Sintilimab-induced swelling along the vessels: Case report

Rationale: Immune-related adverse events are occasionally reported in Sintilimab treatment. This study reports a forward and reverse swelling case along the vein after infusion of Sintilimab. At present, swelling along the vascular direction during peripheral infusion are limitedly reported at home and abroad, especially when choosing a vein with thick, elastic, and good blood return. Patient concerns: A 56-year-old male who suffered from esophageal cancer and liver cancer and received albumin-bound paclitaxel and nedaplatin chemotherapy in combination with Sintilimab immunotherapy appeared swelling along the vessel after infusion of Sintilimab. The patient was punctured 3 times. Diagnoses: Sintilimab-induced vascular edema may be a side effect resulted from a combination of variables such as relatively poor vascular function of the patient, chemical extravasation, allergic skin reactions, venous valves, vascular intima, and diameter stenosis. Sintilimab rarely causes vascular edema only when drug allergic reaction is the underlying factor. As only a few cases of vascular edema caused by Sintilimab have been reported, causes to such a drug-induced vascular edema remained unclear. Interventions: The swelling was controlled by an intravenous specialist nurse according to delayed extravasation treatment and the doctor anti-allergy treatment, but the uncertainty of repeated puncture and symptom diagnosis caused pain and anxiety to the patient and his family. Outcomes: The symptom of swelling was gradually relieved after the anti-allergic treatment. The patient completed the following drug infusion without discomfort after the third puncture. When the patient was discharged the next day, swelling in his both hands disappeared, and the patient had no anxiety or discomfort. Lessons: The side effects of immunotherapy may accumulate over time. Early identification and appropriate nursing management are the keys to minimizing patients’ pain and anxiety. To effectively treat symptoms, nurses could benefit from quickly identifying the source of swelling.


Introduction
Sintilimab, which was the first approval in the world, was accepted as an Investigational New Drug application by The United States Food and Drug Administration in January 2018. Sintilimab is a fully human IgG4 monoclonal antibody that binds to programmed cell death receptor-1, thereby blocking the interaction of programmed cell death receptor-1 with its ligands (programmed cell death 1 ligand 1 and PL-L2) and facilitating the restoration of endogenous anti-tumor T-cell responses. [1] The use of Sintilimab has been widely reported and has shown potent anti-tumor effects. However, its side effects have also been found. [2][3][4][5][6] The current study reported a case of Sintilima-caused adverse reaction in the form of swelling along the vascular direction at the intravenous injection site. However, determining the nature of adverse reactions is still LL  a focus of discussion. Based on this case, we considered the nature of adverse reactions from various aspects and explored the differences between them, hoping to contribute to its early diagnosis, timely management, and the development of critical thinking. The case report guidelines checklist of information was included when writing the case report.

Case presentation
A 56-year-old male presented "swelling along the direction of the vessel" after infusion of Sintilimab. He was diagnosed as "cT4aN-2M0IVA stage of squamous carcinoma of the lower thoracic esophagus and BCLC stage C of primary hepatocellular carcinoma." Since the diagnosis, the patient had received 7 times of transcatheter arterial chemoembolization, 1 time of radiotherapy, and 4 kinds of chemotherapy regimens. He had received 6 cycles of Sintilimab (200 mg) and Lenvatinib, 3 cycles of chemotherapy with albumin-binding paclitaxel and nedaplatin. The patient did not report any skin discomfort during this period. By the time of admission, the treatment was adjusted to chemotherapy combined with immunotherapy (albumin-binding paclitaxel [260 mg] and nedaplatin [80 mg], and Sintilimab [200 mg]). He had completed relevant ultrasound examination to exclude contraindications such as venous thrombosis and venous disease and hematological examination. Moreover, the patient reported a history of diabetes, hepatitis C, and intracranial ischemia but without drug allergy. The main positive symptoms were ascites, eating choking, headache, and esophageal burning. Before using Sintilimab, the patient had no skin discomfort except for erythema. Four minutes after infusion, mild pruritus and swelling appeared around the intravenous infusion along the left upper limb, and the swelling area was about 19 cm × 6 cm ( Fig. 1). Initially, it was considered as drug exudation, and we consulted a specialist nurse and followed her advice to stop the infusion and draw out from the back, elevate the patient limbs, externally apply ice packs and prescribe Xiliaotuo, etc. While the nurse mentioned above followed the drug exudation process, another nurse performed a second puncture at once, helping the patient to complete drug treatment on time. At the same time, they found that the blood returned well (Fig. 2), and speculated that there was no drug exudation. However, immediately after completing the infusion on the right upper limb, a swelling at a size of about 3 cm × 4 cm and 3 cm × 2 cm appeared along the opposite direction of the blood vessels (Fig. 3). On consideration  of the untoward reaction of the skin, the doctor promptly gave the patient anti-allergic treatments such as dexamethasone, diphenhydramine, loratadine, etc. Historical and current information from this episode of care organized as a timeline (Table 1).

Outcome and follow-up
The symptom of swelling were gradually relieved after 5 minutes of anti-allergic treatment. The patient completed the following drug infusion without discomfort after the third puncture. When the patient was discharged the next day, the swelling in both his hands disappeared (Figs. 4 and 5) and the patient had no anxiety or discomfort.

How to define the symptom of swelling along the vascular direction caused by Sintilimab?
Firstly, the nurses considered the swelling at the infusion site as an infusion reaction. According to the hospital venous pipeline management process, we immediately consulted an intravenous specialist nurse for advice. The specialist nurse initially diagnosed it as delayed extravasation, but as the same problem occurred after the treatment and the second puncture, the doctor determined it as an edematous rash. Clinical nurses may not be familiar with edematous rash as an adverse reaction. We found no corresponding instructions from Common Terminology Criteria for Adverse Events5.0 and drug instructions for Sintilimab. From the improvement of symptoms after anti-allergy treatment, we speculated that was an edematous rash. However, it was difficult for us to define this symptom precisely. Currently, adverse reactions to edematous rash have been rarely reported. Study showed that Papular-purpuric gloves and socks syndrome caused by an immune-mediated parvovirus B19 will appear as papules-purpuric edematous rash. Another case was acute transient hepatitis caused by a parvovirus B19 and manifested as an edematous rash on the hands and leg. [7][8][9] Right after the anti-allergic treatment and observation, the symptoms gradually subsided. We assumed that this was drug-induced vascular edema, which we have never met before. Vascular edema induced by Sintilimab may be a complication resulted from multiple factors such as relatively poor vascular conditions, drug extravasation, allergic reactions, venous valves, vascular intima, and diameter stenosis. Drug-induced vascular edema is one of the acquired vascular edemata, which is also known as giant urticaria. It occurs in loose tissues such  as the face, oral mucosa, and hand and foot extremities. About 50 % of patients are often accompanied by urticaria, and anti-allergic drugs or glucocorticoids are usually effective. [10,11] After reviewing previous literature and consulting clinical experts, we determined the symptom as angioedema caused by an allergic reaction to a drug. Few cases of vascular edema induced by Sintilimab have reported. The precise mechanism of such a drug-induced vascular edema was unclear. [12][13][14][15][16][17] The current case contributed to a better understanding on vascular edema induced by Sintilimab. With the increasing benefits of using immunotherapy in anti-tumor therapy, more attention should be given to vascular edema caused by immunotherapy. Furthermore, the case showed that edema at the infusion site can occur to patients who have no previous adverse reactions to drugs.
Recent studies have reported controllable and acceptable skin manifestations, such as pruritus, maculopapular eruption, and that vitiligo-like lesions may appear in the follow-up treatment process. [18][19][20] Sintilimab is now widely used for its easy accessibility, high efficacy, and economic advantages in immunotherapy. However, immune-related adverse events caused by Sintilimab are not controllable. Moreover, the adverse effects of immunotherapy could be cumulative. Therefore, a quick determination of the reason that causes swelling is helpful for nurses to effectively manage patients' symptoms.

What can nurses learn from the case?
We used to evaluate a successful puncture by good blood return and patency. The United States Infusion Nurses Society infusion therapy practice standard of 2021 points out that a successful intravenous infusion includes the return of blood and smooth liquid infusion. [21] However, it is still rare to appear swelling along the direction of blood vessels during intravenous infusion, especially when the vessels are thick and straight with good elasticity and blood return. Mostly, the ability of critical thinking is needed for nurses, which helps them to perform correct assessment and treatment and avoid making wrong clinical decision. [22,23] To some extent, a nurse quick judgment and report allows for positive treatment and contributes to the treatment result for patients. The current case showed that nurses can be recognized for making a positive treatment beneficial to the patient when they were unsure of the diagnosis. Regular monitoring in the process of treatment for early diagnosis and more aggressive application of anti-allergy treatment are preferred methods for managing Sintilimab-induced swelling along the vessels. Early identification and active management by nurses is the key to reducing patients pain and anxiety. Meanwhile, further with clinical cases are needed in the future.
PATIENT PERSPECTIVE: The patient expressed surprise after the occurrence of adverse drug reactions because they had not experienced such symptom before. Though the patient said that he was not satisfied with our treatments because the nurse punctured 3 times on him during the therapy and caused pain to him, he still expressed his understanding for us through constant attention and positive treatment. Judged as an adverse effect of medication and given anti-allergy treatment 16:20 Swelling site gradually subsided 2022/7/7 7:50 Swelling site completely subsided Figure 5. No swelling and pruritus on the right upper limb (7 July, 2022).